The crises in sickle-cell anemia patients are due to sickling of erythrocytes, increase in viscosity, and/or to the gelling of hemoglobin S. These changes occur only when certain factors, i.e. hemoglobin concentrations (A as well as S), fraction present in deoxy form, and temperature, occur at particular combinations of levels, and when thiol reagents, guanidine hydrochloride, and certain short chain alcohols are not present in high concentrations. We propose to approach the understanding of the sickling process by making a systematic study of the rates and degrees of polymerization (aggregation) of purified sickle-hemoglobin in controlled solution environments. Some of the techniques proposed (two of which have already given signs of early success) will permit detection and measurement of the earliest stages of aggregation, at low concentrations, far below those required for the observation of gelling or sickling. It is intended to carry out a rigorously controlled study of the complete range of hemoglobin interactions described in a fragmentary way in the literature, which permit the partial substitution of large amounts of various normal hemoglobins derivatives far smaller quantities of the sickle deoxy hemoglobin in bringing about polymerization and gelling. The effects of other environmental parameters will also be systematically explored. The use of purified hemoglobins A and S (in addition to dialyzed erythrocyte lysates) will permit the effects of other low molecular weight substances including, 2,3 diphosphoglycerate and cyanate, to be investigated. The effects of the latter will be investigated under comparable oxygen transport demand rather than in static systems as in the past. o The phenomenon of gelling will be initially studied largely from the point of view of well-established ideas on the formation of infinite branched networks of high-polymers, which will require close attention to the kinetics of the process. Although no clinical trials or applications are planned, the research may be relevant to the etiology of crisis. Possible examples of relevance are given in the next to last paragraph of the research plan.